Process for the preparation of quinoline-carboxylic acid derivatives

ABSTRACT

The invention relates to a new and simple process for the preparation of quinoline-carboxylic acid derivatives of the general formula (I) ##STR1## as well as hydrates and therapeutically acceptable salts thereof. In the formula the meaning of the substituents is as follows: 
     R is hydrogen atom or a formyl group, 
     R 1  is a hydrogen atom or a straight or branched chain alkyl group having 1 to 4 carbon atoms, which may be substituted by a hydroxyl group, a halogen atom or an amino group; or a CH 3  --NH-group, 
     R 2  is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. 
     According to the invention the compound of the general formula (II) ##STR2## or an acid addition salt thereof is reacted with piperazine in dimethylformamide and--if desired--the compound of the general formula (III) ##STR3## thus obtained is subjected to an acidic or alkaline treatment, or is reacted advantageously with hydrazine or preferably with hydrazine-hydrate.

The invention relates to a new and simple process for the preparation ofquinoline-carboxylic acid derivatives as well as hydrates andtherapeutically acceptable salts thereof. In the formulae the meaning ofthe substituents is as follows:

R is a hydrogen atom or a formyl group,

R₁ is a hydrogen atom or a straight or branched chain alkyl group having1 to 4 carbon atoms, which may be subtituted by a hydroxyl group, ahalogen atom or an amino group; or a CH₃ --NH-- group,

R² is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

The preparation of compounds of the formula (III) ##STR4## was carriedout up to the present by reacting a quinoline-carboxylic acid derivativeof the formula ##STR5## and formyl-piperazine in dimethyl sulfoxide assolvent (Belgine patent specification No. 870576.) Further a process isknown to form the free formyl derivative by formylation with formic acidin a yield of 50% (J. Med. Chem. 23 1358, 1980). This latter process isvery corrosive because of the application of formic acid.

The disadvantage of these processes is that they are carried out inseveral steps and in expensive solvents as pyridine, dimethyl sulfoxide,etc. The yields are very low too.

The present invention relates to a process for the preparation ofquinoline-carboxylic acids of the formula (I) the hydrates and saltsthereof from compounds of the formula (II) in a way, that the compoundof the formula (II) or an acid addition salt thereof is reacted withpiperazine in dimethylformamide and--if desired--the compound of theformula (III) thus obtained is subjected to an acidic or alkalinetreatment, or is reacted advantageously with hydrazine or preferablywith hydrazine-hydrate.

Among the compounds of the formula (I) ##STR6## the1-ethyl-6-fluoro-7-(4-formyl)-piperazinyl-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid possesses a very significant antibacterial effect. It is effectiveagainst Pasteurella multocida in an inhibitioning concentration of 0.25μg/ml, against different Bacillus strains (e.g. Bac. subtilis, Bac.licheniform) in a minimal inhibitioning concentration of 0.5-0.75 g/mland similarly in a minimal inhibitioning concentration of 0.75 μg/mlagainst Shigella sonnei and Salmonella cholerae-suis strains, too.According to the present invention the formylation should be carried outadvantageously by heating.

Higher temperature (120°-153° C.) results in a shorter reaction time.The yield of the reaction can be increased by assuring an acidic medium,the reaction time can be decreased respectively. The acidic medium canbe assured in a way, that the acid addition salt of the compound of theformula (II) is applied, or advantageously the reaction should becarried out in the presence of an acid, advantageously in the presenceof hydrochloric or sulphuric acid.

The processing of the reaction mixture, the recovery of the productoccurs in a very simple way. The dimethylformamide applied as solventand a reagent is removed under reduced pressure and it may be usedrepeatedly. To the residue water is added and the precipitate isrecovered by filtration.

Among the compounds of the formula (I), those of the formula (IV)##STR7## possess valuable antibacterial activities, too (e.g.Antimicrob. Agents Chemother. 1985 581-586). These can be prepared fromcompounds of the general formula (III) containing the formyl group byacidic or alkaline treatment, or advantageously with hydrazine,preferably with hydrazine-hydrate, optionally in the presence of an acid(e.g. acetic acid).

As acids, first mineral acids, e.g. hydrochloric acid, sulphuric acid,phosphoric acid, etc. are applied in a suitable dilution. As alkali thehydroxides and carbonates of the alkali and alkali earth metals areapplied. The removal of the formyl group is carried out in an organicsolvent and/or in water. advantageously in an alcohol-water mixture. Themost advantageous was a 3:1 mixture of isopropyl alcohol and water. Thereaction is carried out at a temperature of 25°-100° C., advantageouslyat the boiling point higher temperature results in a decreased reactiontime.

The product can be obtained advantageously after the neutralization ofthe acid or alkali excess of the reaction mixture by filtration. Ifdesired the product can be purified by recrystallization. The compoundsof the formula (I) can be prepared in the form of hydrates, or thehydrates can be formed they can be set free from their saltsrespectively, or their therapeutically accepable salts can be formed.

A significant moment of the present process is the recognition, thatfrom the compound of the formula (III) the formyl group can be removedby reacting with hydrazine. This way we succeeded to a realize a newtype process, which leads to a more uniform and pure product compared tothe hydrolysis processes.

Further details of the present process are shown in the example, withoutlimiting the application to the examples.

EXAMPLE 1

5.4 g (0.02 moles) of1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acidand 10.4 g (0.12 moles) of piperazine in 120 ml of dimethylforrmamideare heated for 6 hours at 145° C. Thereafter the solvent is removedunder reduced pressure and 300 ml of water are added to the residue. Theprecipitate is obtained by filtration. Thus 4.6 g of1-ethyl-6-fluoro-7-(4-formyl)-piperazinyl-1,4-dihydro-4-oxo-quinoline-3-carbocyclicacid are obtained, melting at 270° C. After recrystallisation fromdimethylformamide the melting point raised to 285°-286° C.

EXAMPLE 2

1.0 g (0.0029 moles) of1-ethyl-6-fluoro-7-(4-formyl)-piperazinyl-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid is suspended in 40 ml of a 3:1 mixture of isopropyl alcohol andwater and 10 ml of 1N hydrochloric acid are added. The reaction mixtureis boiled for 5 hours. After cooling the product crystallizes in theform of a hydrochloric acid salt and can be removed by filtration, orafter neutralization with a 1N sodium hydroxide solution theprecipitated product is filtered. After drying 0.58 g of1-ethyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxo-quionoline-3-carboxylicacid are obtained, melting point 222° C.

EXAMPLE 3

1.0 g (0.0029 moles) of1-ethyl-6-fluoro-7-(4-formyl)-piperazinyl-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid is suspended in 40 ml of a 3:1 mixture of isopropyl alcohol andwater and 5 ml of an aqueous 1N sodium hydroxide solution are added. Thereaction mixture is boiled for 8 hours. After cooling the solution isneutralized with a diluted hydrochloric acid solution. The precipitatedproduct is filtered. The resulting 0.6 of1-ethyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid melts at 218° C.

EXAMPLE 4

1.0 g (0.0029 moles) of1-ethyl-6-fluoro-7-(4-formyl)-piperazinyl-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid is suspended in 50 ml of a 3:1 mixture of isopropyl alcohol andwater and 0.5 ml (0.010 moles) of a 98% hydrazine-hydrate and 0.6 ml(0.010 moles) of acetic acid are added. The reaction mixture is heatedat 100° C. for 6 hours. The product crystallizing from the cooledsolution is obtained by filtration. Thus 0.827 g of the1-ethyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid melting at 222° C. are obtained.

EXAMPLE 5

1.35 g (0.005 moles) of1-ethyl-6fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid,2.6 g (0.03 moles) of piperazine and 1 ml of a concentrated hydrochloricacid are heated at boiling temperature in 30 ml of dimethylformamide for4 hours. The solvent is removed under reduced pressure and to theresidue 80 ml of water are added. The precipitated product is filteredand washed with water. After drying 1.42 g (82%) of1-ethyl-6-fluoro-7-(4-formyl)-piperazinyl-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid are obtained melting at 288° C.

We claim:
 1. A process for the preparation of a compound of the Formula(I) ##STR8## or a hydrate or a pharmaceutically acceptable salt thereofwherein R is hydrogen or formyl;R¹ is hydrogen, C₁ to C₄ straight orbranched chain alkyl unsubstituted or substituted by halogen, hydroxy oramino, or methylamino; and R² is hydrogen or lower alkyl; whichcomprises the steps of: (a) aminating a compound of the Formula (II)##STR9## with piperazine in dimethylformamide, said dimethylformamideserving as both a solvent and as sole formylating reagent to N-formylatethe 4-position of the piperazine, to produce the compound of the Formula(I) where R is formyl; and in the case wherein the compound of theFormula (I) includes R as hydrogen; and (b) treating the compound of theFormula (I) where R is formyl with an acid or with an alkali or withhydrazine or hydrazine hydrate to yield the desired product.
 2. Theprocess defined in claim 1 wherein according to step (a) the aminationof the compund of the Formula (II) with piperazine and dimethylformamideis carried out in an acidic medium.
 3. The process defined in claim 1wherein according to step (b) the compound of the Formula (I) where R isformyl is treated with a mineral acid or an alkali.
 4. The processdefined in claim 1 wherein according to step (b) the hydrazinic, acidicor alkaline treatment of the compound of the Formula (I) where R isformyl is carried out in a mixture of isopropanol and water.
 5. Theprocess defined in claim 1 wherein according to step (b) the treatmentof the compound of the Formula (I) where R is formyl is carried out withhydrazine or hydrazine hydrate to yield the compound of the Formula (I)where R is hydrogen.
 6. A process for the preparation of a compound ofthe Formula (IV) ##STR10## or a hydrate or a pharmaceutically acceptablesalt thereof wherein R¹ is hydrogen, C¹ to C⁴ straight or branched chainalkayl unsubstituted or substituted by halogen, hydroxy or amino; ormethylamino; andR² is hydrogen or lower alkyl; which comprises the stepsof: (a) aminating a compound of the Formula (II) ##STR11## withpiperazine in dimethylformamide, said dimethylformamide serving as botha solvent and as sole formylating reagent to N-formylate the 4-positionof the piperazine, to produce the compound of the Formula (III)##STR12## and (b) treating the compound of the Formula (III) withhydrazine or hydrazine hydrate to yield the desired compound.